A complex series of events are necessary for effective healing of human wounds. There are resident populations of gamma delta and alpha beta T cells in human epidermis and dermis, but the role of these T cells in wound healing has not been examined. We have determined that mice lacking skin gamma delta T cells have defects in keratinocyte proliferation, tissue reepithelialization, and inflammation following wounding. This raises the possibility that skin gamma delta T cell production of specific growth factors, chemokines, and other factors may be critical for effective human wound healing. Our hypothesis is that there are functional differences between the skin-resident intraepithelial alpha beta and gamma delta T cell populations and the circulating T cells that migrate into wounds. We hypothesize that skin-resident T cell recognition of antigen expressed by injured keratinocytes stimulates production of factors which directly initiate wound repair as well as modulate function of neighboring cells and direct infiltrating cells to sites of damage. The absence or aberrant function of these skin-resident T cells would impact repair and may contribute to delayed healing and non-healing wounds. Chronic non-healing wounds have a significant impact on patient well being and on costs to the health care system. Delayed healing of burn wounds contribute to morbidity and subsequent mortality of thermally injured patients. The goal of these studies is to investigate the role of epithelial-resident human skin T cells in wound healing. We have established a collaboration between clinicians and basic scientists to determine if T cells that are resident in human skin participate in effective wound healing. We will determine the mechanisms of skin T cell function in wound healing and determine if these functions are unique to skin-resident T cells. We will determine if skin-resident T cells are dysfunctional in non-healing wounds and the mechanisms of the defects. Finally we will determine if activated skin-resident T cells can accelerate or restore delayed wound healing. If T cells are defective in chronic or non-healing wounds, new strategies will be tested to determine if restoration of normal, functional T cells will improve or accelerate wound healing. PUBLIC HEALTH RELEVANCE: Over 4 million patients in the U.S. are afflicted with chronic wounds that contribute to morbidity and mortality. The proposed studies should provide a greater understanding of the functions of skin- resident T cells in wound healing and results will determine the clinical potential of exploiting these cells to develop new strategies for treatment of non-healing wounds.